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11-1-2016

Toxic environmental exposures and kidney health in children.

Darcy K. Weidemann Children's Mercy Hospital

Virginia M. Weaver

Jeffrey J. Fadrowski

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Recommended Citation Weidemann, D. K., Weaver, V. M., Fadrowski, J. J. Toxic environmental exposures and kidney health in children. Pediatric nephrology (Berlin, Germany) 31, 2043-2054 (2016).

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Author ManuscriptAuthor Manuscript Author Pediatr Manuscript Author Nephrol. Author Manuscript Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Pediatr Nephrol. 2016 November ; 31(11): 2043–2054. doi:10.1007/s00467-015-3222-3.

Toxic environmental exposures and kidney health in children

Darcy K. Weidemann1, Virginia M. Weaver2,3, and Jeffrey J. Fadrowski3,4 Darcy K. Weidemann: [email protected] 1Division of Pediatric Nephrology, Children’s Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108, USA 2Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 3Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA 4Division of Nephrology, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA

Abstract High-level exposures to a number of agents are known to have direct nephrotoxic effects in children. A growing body of literature supports the hypothesis that chronic, relatively low-level exposure to various nephrotoxicants may also increase the risk for chronic kidney disease (CKD) or accelerate its progression. In this review we highlight several environmental nephrotoxicants and their association with CKD in children and adolescents. We also discuss unique epidemiological challenges in the use of kidney biomarkers in environmental nephrotoxicology.

Keywords Aristolochic acid; Arsenic; Cadmium; Chronic kidney disease; Environmental nephrotoxicants; Lead; Melamine

Introduction More than 84,000 new synthetic chemicals have been registered with the U.S. Environmental Protection Agency (EPA) over the past 40 years, almost 3000 of which are classified as high production volume (HPV) chemicals, with ≥1 million pounds produced per year [1]. These chemicals are widely dispersed in the environment, and children may be exposed via air, drinking water, and food. Measurable quantities of 200 HPV chemicals are routinely detected in the blood and urine of virtually all Americans, as well as in breast milk and cord blood [2]. A large proportion of these chemicals remain untested for their potential toxic effects in children.

Correspondence to: Darcy K. Weidemann, [email protected]. Conflict of interest The authors declare no conflict of interest. Weidemann et al. Page 2

A number of environmental agents have been shown to demonstrate acute and/or chronic Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author nephrotoxicity (Table 1). Limited data exist for children; much of the research has been performed in adults or animal studies. However, children experience unique patterns of environmental exposures and exhibit biological susceptibilities that may affect their risk for toxicity following exposure. In this review we highlight several environmental nephrotoxicants and their association with kidney disease in children.

Children: a vulnerable population Fetal determinants Nephrogenesis occurs from the 6th to the 36th weeks of gestation; after 36 weeks nephrogenesis is generally complete, and each kidney has a full complement of nephrons (on average approximately 1 million nephrons per kidney). Factors affecting nephron endowment include genetics and environmental exposures, such as maternal malnutrition, gestational diabetes, uteroplacental insufficiency, maternal or fetal drug exposure, and premature birth [3]. Following birth, there is a rapid increase in glomerular filtration rate (GFR) and a decrease in renal vascular resistance in response to an increase in mean arterial pressure. The GFR averages about 55 mL/ min/1.73 m2 by 2 weeks of age and reaches adult capacity of 100–125 mL/min/1.73 m2 around 2 years of age [4]. Exposure to nephrotoxic agents during kidney development can result in a reduction in nephron number, as well as disruption of nephron structure and/or function [5]. The kidney does not have the ability to regenerate nephrons. Although the GFR in single nephrons can increase in response to damage to other nephrons, this adaptive capacity is not unlimited. Therefore, once a critical mass of nephrons has been damaged, the kidney’s ability to compensate is overwhelmed, resulting in a decrease in kidney function. In this context it is not surprising that any insult to the developing kidney that impacts nephron development can subsequently increase risk for chronic kidney disease (CKD).

Postnatal determinants In environmental and occupational medicine, children are often considered to be a particularly vulnerable population. Children experience proportionally greater exposures on a body-weight basis. For example, infants inhale twice as much air and a 6-month-old infant drinks sevenfold more water and consumes three- to fourfold more calories per body surface area than adults [6]. Additionally, children may experience more exposure due to the consumption of to certain “favored foods” (e.g., milk, formula, or fruit juice) which may contain pesticides and age-related behaviors, such as increased hand-to-mouth activity and more time spent on the floor. The fetus and infant may also be especially vulnerable to substances that disrupt developmental processes during sensitive time windows of target organ development [7]. The ability of children to respond to environmental toxicants also differs from that of adults due to relatively immature metabolic pathways, especially in the first few months after birth. Age-dependent differences exist between children and adults which can affect the absorption, distribution, metabolism, and excretion of potential toxicants [8]. The kidney is one of the main excretory organs of the body; however, many renal excretory pathways are not fully mature in the first year of life [9]. The kidneys are susceptible to toxic injury, in part because although they have a relatively low proportion of

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body mass, they receive 20–25 % of cardiac output. Due to the high metabolic activity and Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author active uptake by tubular cells, the proximal tubular epithelium is particularly susceptible to toxic injury, although vulnerabilities to various nephrotoxic agents have been described in all parts of the nephron (Fig. 1). Therefore, the kidney may be a vulnerable target of toxicants, particularly in children.

Heavy metal nephrotoxicants High-level exposure to many of the heavy metals discussed below increases risk for acute kidney injury. Although exposure at high levels is increasingly uncommon in the industrially developed countries, there is increasing recognition that chronic exposures to lower levels of environmental nephrotoxicants may also contribute to kidney injury and increased risk for CKD. Low-level or “environmental” exposures to these chemicals are widespread in the modern world. The proximal tubular cell is the presumed target of action for the majority of heavy metals. The cellular mechanisms underlying nephrotoxicity remain incompletely described, and a review of this literature is beyond the scope of this review. Common mechanisms described or postulated include oxidative stress with associated lipid peroxidation, apoptosis, and cellular necrosis [10].

Arsenic High-dose intoxication by inorganic arsenic is known to cause acute kidney injury [11], including tubulointerstitial nephritis and acute tubular necrosis [12]. Chronic environmental exposure occurs via contaminated drinking water and food. Contaminated sources can be traced to the past use of copper chromated arsenate as a wood preservative in pressure- treated lumber, occupational sources in mining and smelting, industrial applications, and the agricultural use of pesticides, fertilizers, and antimicrobial additives for animal and poultry feed [11]. In the USA, the EPA has established the standard arsenic limit in water at 10 μg/L, although millions of individuals are estimated to live in an area that exceeds this standard [13].

Several recent studies, primarily done in adults, suggest that chronic low-level exposure to arsenic may be associated with CKD [14]. A cross-sectional analysis of 3851 adults participating in the Strong Heart Study in the USA reported an adjusted odds ratio of prevalent CKD comparing the 75th to 25th percentile of arsenic exposure (defined as the sum of inorganic and methylated arsenic) to be 0.7 [95 % confidence interval (CI) 0.6–0.8]. In contrast, prospective analysis of 3119 of these participants demonstrated a positive relationship between urinary arsenic and incident CKD, with an adjusted hazard ratio of 1.2 (95 % CI 1.03–1.41) [15]. The discrepancy between the cross-sectional and prospective findings was attributed to reverse causation, in that reduced GFR leads to impaired inorganic arsenic excretion at baseline. A community-based survey of 1043 Taiwanese adults found a graded, dose-related increase in the odds of elevated β2-microglobulin and an estimated GFR (eGFR) value of≤ 90 mL/min/1.73 m2 as urinary total arsenic levels increased above the reference group (≤35 μg/g creatinine) [16]. A case–control study of 125 patients with CKD (mean eGFR 28 mL/ min/1.73 m2) and 229 age-matched controls (mean eGFR 80 mL/min/1.73 m2) showed that total urinary arsenic level was significantly associated with

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CKD in a dose–response relationship, with those in the highest tertile of total arsenic having Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author 4.3 (95 % CI 1.9–9.7) higher odds of CKD versus controls [17]. Estimated GFR was also significantly negatively associated with total urinary arsenic concentrations in another case– control study of 132 patients with renal cell carcinoma, as compared to age- and sex- matched controls [18]. In Antofagasta, Chile, arsenic exposure from the public water supply occurred from 1958 up to 1970, after which time arsenic mitigation efforts began. This presented a unique scenario, rare in environmental epidemiology, with a known exposure time period and large study population (125,000 in 1970). Increased mortality from bladder cancer [standardized mortality rate (SMR) 18.1; 95 % CI 11.3–27.4] and chronic kidney disease (SMR 2.0; 95 % CI 1.5–2.8) was observed in young adults aged 30–49 years in who were exposed to high arsenic levels (mean 870 μg/L) in utero and/or≤18 years of age during the high exposure time period of 1958–1970 [19].

Studies of the impact of arsenic on kidney function in children are relatively rare. A 2006 cross-sectional study of more than 800 European children found no relation between inorganic arsenic and various serum markers of GFR (creatinine, cystatin C, or β2 microglobulin) [20]. A follow-up of 1887 children enrolled in the MINIMat study in Bangladesh (a country with endemic high arsenic exposure) who were exposed to arsenic and cadmium in utero found modest increases in blood pressure (3.7 mmHg systolic and 2.9 mmHg diastolic) per 1 mg/L increase in maternal urinary arsenic during pregnancy [21]. However, a recent follow-up of this cohort found a negative association between urine cadmium and eGFR, but no relationship with arsenic [22]. A recent cross-sectional examination of 1253 participants in the National Health and Nutrition Examination Survey (NHANES) aged 12–30 years found a positive relationship between arsenic and eGFR, but only when results were corrected for urinary concentration by urinary creatinine, not by urine osmolality [23].

Cadmium Cadmium is another well-known nephrotoxicant that targets the proximal tubule in the kidney. Exposure occurs through fossil fuel combustion, agricultural use of phosphate fertilizers, tobacco smoking, and various occupational exposures, including battery manufacture, copper and zinc smelting, and welding [24]. In the USA, the largest source of cadmium exposure for nonsmoking adults and children is through dietary intake of contaminated food and water. In contrast to lead, exposure to secondhand smoke has not been associated with elevated urinary cadmium levels in children [25]. Cadmium bioaccumulates in the liver and kidney, and therefore cadmium levels in urine are thought to be a good biomarker of the cumulative internal dose and kidney and body burden of cadmium, whereas blood levels are thought to be more indicative of recent exposure. Longitudinal studies in occupationally exposed workers and people with high environmental exposures to cadmium have reported these populations to have an increased risk for CKD [26, 27]. Cross-sectional studies have also reported nephrotoxicity at lower levels of exposure to cadmium [28-30], and, with co-exposure to lead, an increased risk for albuminuria and CKD [30].

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Results have been mixed among studies that have examined GFR measures and/or Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author albuminuria in children. A study of 200 Belgian adolescents living near a lead smelter showed no association between blood or urine cadmium levels and serum cystatin C levels [31]. In the European cohort study of 804 children mentioned in the preceding section, higher urine cadmium levels were associated with lower serum creatinine, which is a finding opposite from that expected in nephrotoxicity [20]. There was no association between urine cadmium levels and serum β2-microglobulin or cystatin C levels, although higher levels of blood and urine cadmium were associated with higher levels of retinol-binding protein and N-acetyl-β-D-glucosaminidase (NAG). A study of adults and children residing near a zinc smelter and a control group reported no associations between urine cadmium levels and NAG or albuminuria in 159 children aged 6–17 years, although a positive association between these was observed in 150 adults [32]. Finally, the MINIMat study of 1,06 rural Bangladesh preschool children found that, at levels>0.12 μg/L, a 0.5 μg/L increase in urinary cadmium was associated with a decrease in eGFR of 2.6 mL/min/ 1.73 m2 in girls [22].

Lead Lead is the most notable and best studied environmental nephrotoxicant. Environmental levels of lead have increased more than 1000-fold over the past three centuries as a result of human activities, including the Industrial Revolution, leaded gasoline, lead-based paint, mining operations, plumbing, and other industrial applications [33]. Acute lead poisoning (blood lead levels>80–100 μg/dL) disrupts both proximal tubular structure and function. Histologically, acute lead poisoning leads to the development of intranuclear inclusion bodies containing lead–protein complexes and mitochondrial swelling in proximal tubular cells [34]. The molecular mechanism of toxicity is thought to involve the effects of lead on mitochondrial respiration and phosphorylation [35]. Clinically, acute lead poisoning is characterized by the development of glucosuria, aminoaciduria, phosphaturia, or Fanconi’s syndrome. Lead is bioaccumulative, with detectable lead levels in the bones of chronically exposed children and adults which can be mobilized by the body and contribute to ongoing endogenous exposure [36]. Lead poisoning is also known to reduce 1,25-dihydroxyvitamin D synthesis [37] and has been associated with bone demineralization and rickets in children [38]. The kidney manifestations of acute lead poisoning are usually reversible after cessation of lead exposure and, if indicated, chelation therapy [35, 39].

Chronic lead poisoning (blood lead levels>60 μg/dL) has been reported in children and adults and may result in lead nephropathy [40], which is characterized by tubulointerstitial fibrosis, tubular atrophy, glomerular sclerosis, and ultimately diminished GFR (Fig. 2) [41, 42]. Inflammatory cells are typically absent, and intranuclear inclusion bodies are also often absent [42]. Chronic lead exposure has also been shown to cause hypertension in animal models [43] and humans [44].

Chronic lead nephropathy in young adults was first described in 1929 after an outbreak of lead poisoning in children in Queensland, Australia due to the ingestion of lead-based paint [45]. A follow-up study in 1954 of 401 young adults diagnosed with lead poisoning in childhood between 1915 and 1935 revealed that 165 individuals had died in young adulthood, of whom 108 deaths were due to nephritis or hypertension, an incidence which

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far exceeded that in the rest of Australia [46]. The kidneys of these individuals were found to Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author be contracted and small, with histologic changes of interstitial fibrosis, hypertensive vascular changes, and “alterative glomerulitis” [47, 48], which is a term coined by Kimmelstiel and Wilson in 1936 to describe histological findings of nuclear proliferation and irregular pyknotic nuclei in the glomerular tuft adjacent to the vascular pole seen in hypertension- induced glomerulosclerosis [49]. Although subsequent studies of adults who suffered childhood lead poisoning have reported hypertension [50, 51], persistent partial Fanconi’s syndrome [52], and individual cases consistent with lead nephropathy [50], they have not demonstrated overall increased mortality or statistically significant decreased kidney function [53]. A possible explanation for this discrepancy may be that the children in the Queensland epidemic were untreated, whereas children in subsequent studies were treated with chelation therapy. Hyperfiltration may also be a factor in these disparate findings. Hyperfiltration is a complex phenomenon described in multiple pathophysiological states (including diabetes, sickle cell disease, and obesity) characterized by maladaptive alterations in glomerular hemodynamics and structural changes within the glomerulus; it is often associated with albuminuria and a transient increase in GFR [54]. Lead has also been implicated as a cause of hyperfiltration in both animal models [55] and human studies [40, 56]. The substantial nephron reserve and lack of sensitive outcome measures may be additional factors that contribute to the challenges of linking lower level toxicant exposures to kidney disease.

More recent investigations of childhood effects of lead on kidney outcomes have focused on participants living in close proximity to industrial pollution sources. Contradictory results have been reported. In a study of 200 Belgian adolescents, classified into a rural control group and two exposed groups from industrialized suburbs, blood lead level was positively associated with serum cystatin C level, with mean blood lead levels of 1.5, 1.8, and 2.7 μg/dL, respectively [31]. In contrast, negative associations with serum creatinine and cystatin C were reported in a cross-sectional survey of 804 European children, with mean blood lead levels ranging from 2.8 to 6.5 μg/dL [20]. The authors of the latter study implicated hyperfiltration as potential explanation for these contradictory findings. In unadjusted analyses in other populations of exposed children, blood lead levels were positively associated with a variety of urinary biomarkers, including retinol-binding protein [57], beta2-microglobin and Clara cell protein [58], and NAG [59]. A prospective Yugoslavian birth-cohort study identified significant increases in blood pressure and proteinuria with higher blood lead levels in 577 children born to women living near a lead smelter, refinery, and battery plant [60].

Fortunately, mitigation efforts in the USA and worldwide have significantly reduced childhood exposure to lead over the past 50 years [61]. Although stringent control measures have been enacted in the last few decades, lead still persists in the soil and to a lesser extent in the air and water (and consequently in the food chain), with potential consequences of chronic, low-level environmental exposure. Thus, research efforts have more recently focused on populations with lower levels of environmental exposure to lead. Multiple cross- sectional studies in adults have demonstrated a significant positive association between blood lead level and serum creatinine [62-64], as well as increased all-cause and cardiovascular mortality [65]. An analysis of 769 adolescents participating in the 1988–1994

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NHANES with median blood lead and cystatin C-based eGFR levels of 1.5 μg/dL and 112.9 Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author mL/ min/1.73 m2, respectively, identified a statistically significant, negative association between blood lead level and kidney function [66]. In fully adjusted models, cystatin C- based eGFR was lower (−6.6 mL/min/1.73 m2; 95 % CI −0.7 to −12.6) in children with lead levels in the highest quartile (≥3.0 μg/dL) compared with those in the lowest quartile (<1 μg/ dL). A doubling of blood lead level was associated with a lower cystatin C-based eGFR (−2.9 mL/min/1.73 m2; 95 % CI −0.7 to −5.0). The association with serum creatinine-based eGFR was also negative but did not reach statistical significance.

The association between lead exposure and GFR was evaluated in a potentially more vulnerable population of North American children with CKD in the Chronic Kidney Disease in Children (CKiD) study. Median blood lead level and measured GFR were 1.2 μg/dL and 44 mL/min/1.73 m2, respectively. The average percentage change in GFR for each 1 μg/dL increase in blood lead level was −2.1 (95 % CI −6.0 to 1.8). In analyses stratified by CKD diagnosis, the association between lead level and GFR was stronger among children with glomerular disease underlying CKD; in this group, each 1 μg/dL increase in lead level was associated with a −12.1 (95 % CI −22.2 to −1.9) percentage change in GFR [67]. Significantly elevated lead levels have also been reported in other pediatric CKD populations. Filler et al. reported a significantly higher mean blood lead level in 16 patients (9 on hemodialysis, 1 on peritoneal dialysis, and 6 at CKD stage 3 or 4)compared to 647 healthy controls without kidney disease (21.1±15.8 vs. 6.35 μg/L, respectively) and correlated these with calcium carbonate dose and GFR [68].

The hypothesis of reverse causality attributes higher lead levels to reduced lead excretion as a consequence—rather than cause—of decreased kidney function and is raised as an explanatory factor for negative associations between higher blood lead and kidney function in cross-sectional studies. Longitudinal studies are useful to address the potential impact of this mechanism on associations between lead and kidney function. In a prospective study of 121 patients with CKD, a 1 μg/dL increase in blood lead level was associated with a 4.0 mL/min/1.73 m2 decline in GFR over 48 months of observation [69]. Longitudinal data on children are scarce. A study in which lead exposure was assessed by lead content in deciduous teeth observed higher levels in 22 German children with CKD compared to a control group of 20 siblings or neighbors and another group of 16 healthy children without known lead exposure (2.8, 1.7, and 1.4 μg/g, respectively [70]. Importantly, lead level in teeth was not correlated with duration of kidney function impairment, providing evidence against reverse causality.

In a series of randomized experimental trials, a research group in Taiwan observed that chelation with EDTA slows CKD progression in adults, even at lead levels considered to be normal [71]. The same group reported an increase in GFR of 6 mL/min/1.73 m2 in a group of diabetic CKD patients treated over 2 years with chelation therapy (average of 7.0 g 2 CaNa2EDTA) compared to a GFR decline of 1.4 mL/min/ 1.73 m in the untreated group [72]. However, this research is preliminary and requires replication in other populations, including children, before chelation at lower lead levels can be recommended [73].

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Mercury Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author Mercury exposure occurs through the oral, inhalation, and dermal routes, with distinct clinical toxidromes related to the three forms of mercury: elemental, inorganic, and organic. Exposure to elemental mercury by inhalation can occur from breathing mercury vapor emitted from coal-fired power plants, cinnabar ore smelting and gold extraction/processing plants, dental amalgams, thermometers, and caustic soda production. Acute exposure to mercury vapor may result in chemical pneumonitis; chronic exposure may cause excessive salivation, intention tremor, and myriad psychiatric symptoms. Inorganic mercury exposure occurs via mercury mining (cinnabar ore) and from a variety of medicinal uses; for example, skin lightening creams and, historically, calomel powder used for teething in small children. Exposure in children may result in acrodynia (Pink disease), characterized by red discoloration of the skin of the hands and feet, fever, profuse sweating, photophobia, and psychiatric manifestations [74]. Dietary sources of seafood are a major source of organic mercury compounds, notably methyl mercury, which is a particular health hazard to infants and the developing fetus.

Mercury exposure has two distinct nephrotoxic effects: (1) acute kidney injury and proximal tubule damage; (2) rarely, an immune-complex-mediated nephrotic syndrome which has been described in animal models [75] and humans [76]. Age-related differences in kidney function may influence mercury toxicity. Animal data suggest that immature kidneys may have decreased tubular transport, and therefore less mercury excretion, which may increase toxicity [5].

Amalgam dental fillings contain elemental mercury and are a common source of environmental exposure in the general population. Several recent studies have examined the impact of these fillings on kidney function in children. The New England Children’s Amalgam Trial enrolled 534 children, 6–10 years of age, who had at least two cavities but no prior amalgam fillings, and randomized them to receive either amalgam or resin composite fillings [77]. Follow-up over 5 years showed no significant differences between treatment groups in average levels of urine biomarkers (α1-microglobulin, gamma-glutamyl transpeptidase, and NAG), although a significantly increased prevalence of microalbuminuria in the amalgam group in years 3–5 (adjusted odds ratio 1.8; 95 % CI 1.1– 2.9) was observed. The authors noted that microalbuminuria was present in years 3 and 5 in ten children in the amalgam group compared to only two children in the composite group (p value0.04). The Casa Pia trial, in which 507 children, randomized to amalgam or composite resin fillings, were enrolled, revealed no significant differences in albuminuria and other markers by treatment group over the 7-year follow-up period [78]. However, a subsequent posthoc analysis of the same dataset using an alternative statistical approach demonstrated statistically significant dose-dependent correlations between cumulative mercury exposure and urinary glutathione-S-transferase-alpha, a urinary biomarker of proximal tubule injury [79]. This posthoc analysis has been criticized by the authors of the parent study as employing a flawed statistical approach [80]. Continued longitudinal follow-up of children in the experimental studies would be of interest, as would an examination of GFR measures.

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Uranium Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author Renal toxicity is considered to be a hallmark of uranium poisoning and is well-established in multiple experimental animal studies [81, 82]. Exposure occurs via groundwater contamination from natural uranium deposits, as well as from uranium mining, milling, and processing. Uranium bioaccumulates in bone, although to a lesser extent than lead. The S3 segment of the renal proximal tubule is a target site of involvement, resulting in tubular dysfunction. Epidemiological data are scarce and have not shown consistent findings with GFR, although there is some limited evidence of urinary biomarkers indicating proximal tubular damage [83]. A follow-up of 35 Gulf War veterans exposed to depleted uranium showed a trend towards increased levels of β2-microglobulin and retinal binding protein levels in the highest uranium exposure group, although there was no association with GFR [84]. A case study of a family exposed to naturally uranium-contaminated well-water also demonstrated elevated β2-microglobulin in the youngest child, suggesting that young children may be particularly vulnerable [85]. The child’s β2-microglobulin level subsequently declined after cessation of exposure. Age-related differences in kidney toxicity have also been reported in animal models [5].

Naturally occurring chemical nephrotoxicants Aristolochic acid nephropathy Aristolochic acid is a naturally occurring toxic compound found in plants of the Birthwort (Aristolochiaceae) family that includes the Asarum (wild ginger) genus and Aristolochia genus. Herbal drugs derived from plants belonging to genus Aristolochia have been used since antiquity for treating snake bites, obstetrics, arthritis, gout, and rheumatism, and in some parts of the world Aristolochia plants and their extracts are used in traditional Chinese herbal medications [86]. Aristolochic acid has been implicated as the cause of end-stage renal disease (ESRD) in a 10-year-old child [87], as well as the causative agent in Balkan endemic nephropathy and Chinese herb nephropathy [88]. Balkan endemic nephropathy was described in the 1950s among several communities near tributaries of the Danube River in the Balkan Peninsula and is characterized by a chronic tubulointerstitial renal disease with increased risk for urothelial carcinoma. Heavy metals, viruses, trace-metal deficiencies, and mycotoxins (especially ochratoxin A) were considered as possible etiologies, but most experts now agree that chronic exposure to dietary aristolochic acid was the likely cause [88]. In 2001 the U.S. Food and Drug Administration advised consumers of the risks of botanical products containing aristolochic acid due to the risk of permanent kidney damage (including ESRD) and certain types of cancers occurring in the urinary tract [89]. The exact mechanism of action of nephropathy remains unknown, although formation of unique aristolochic acid–DNA adducts in human kidney cells as well as mutation of the tumor suppressor gene TP53 have been implicated in carcinogenesis [90].

Mycotoxins Mycotoxins are secondary metabolites produced by several species of fungi which are capable of causing disease in human or animal species. Ochratoxin A and citrinin are two such mycotoxins isolated from Penicillium, Aspergillus, and Monascus species with known nephrotoxicity in multiple animal models, although the significance for the human

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population remains unknown [91]. They have been found in many human foods, including Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author wheat, oats, rye, barley, and rice. Citrinin and ochratoxin A have also been implicated as a cause of Balkan nephropathy and yellow rice fever [91]. Animal studies have demonstrated citrinin transport via the organic anion transporter in the proximal tubule cell [92], as well as synergistic disruption of RNA synthesis in murine kidneys by citrinin and ochratoxin A [91].

Synthetic nephrotoxicants Melamine nephropathy Melamine is a synthetic chemical with multiple commercial applications, including manufacture of colorants, glues, laminates, adhesives, production of dinnerware, dry-erase boards, cleaning products (such as Magic Eraser), and flame retardants [93]. Although not intended for human consumption and banned by the World Health Organization, melamine has a high nitrogen content and is known to falsely inflate the protein content in foodstuffs. It has been used to deliberately adulterate animal and human foods in an effort to lower production costs. Several well-publicized outbreaks of kidney failure and kidney stones in animals and humans have been reported in the last decade, with one such outbreak in 2007 resulting in a widespread pet food recall and the Chinese epidemic of 2008, involving the consumption of melamine-tainted infant formula, affecting over 294,000 infants and children, 51,900 of whom required hospitalization and at least six of whom died [94].

The mechanism of melamine nephrotoxicity in pet and livestock outbreaks is related to its ability to react with cyanuric acid in the bloodstream and form large round melamine– cyanuric acid crystals which lead to urinary obstruction and acute kidney injury [93]. The formation of these crystals has been associated with extremely high mortality in animal outbreaks. In the tainted Chinese infant formula outbreak, the kidney stones were composed primarily of melamine and uric acid and, consequently, they were radiolucent and not visible on plain X-ray films [95]. Symptoms included irritability, dysuria, renal colic, hematuria, stone passage, and, rarely, symptoms of acute kidney injury related to urinary obstruction, including elevated creatinine, hypertension, edema, and/or oliguria. Acute kidney injury occurred in 2.5 % of cases [95].

Other CKD of unknown etiology An epidemic of CKD of unknown etiology, termed “Mesoamerican nephropathy”, has recently been described to disproportionately affect young to middle-aged Central American agricultural workers without traditional risk factors for kidney disease, such as diabetes or hypertension [96]. Symptoms are suggestive of nonglomerular disease, as patients present without significant proteinuria or hypertension, small echogenic kidneys are seen on ultrasound imaging, and biopsy findings indicate the presence of chronic tubulointerstitial disease [97]. A frequent symptom complex identified among individuals is chistata which is a colloquial term in Central America for dysuria. Similar patterns of kidney disease in adults without traditional risk factors have been reported in Sri Lanka, the state of Andhra Prakesh in India, and the El-Minia Governorate in Egypt. Given that the cause(s) remains

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uncharacterized, it has been labeled CKD of unknown etiology (CKDu). Tragically, as the Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author disease occurs in communities in which dialysis and transplantation are not routinely available, CKDu is often considered to be a terminal diagnosis. Although the etiology remains unknown, multiple hypotheses have been proposed, including chronic dehydration from hard labor, agrochemicals (such as pesticides), heavy metals, aristolochic acid, medications [nonsteroidal anti-inflammatory drugs (NSAIDs), and/or infections, such as leptospirosis [98]. Although this disease typically affects adults in their third to fifth decade of life, pediatric cases have been reported [99]. A preliminary study in which four urinary biomarkers of early-stage kidney damage [neutrophil gelatinase-associated lipocalin (NGAL), NAG, interleukin-18 (IL-18), and albumin/creatinine ratio] were assessed in 245 Nicaraguan adolescents found evidence of elevated IL-18 levels relative to those in healthy participants in other countries [100]. The prevalence in children may be underestimated given the challenges in characterizing and detecting the disease, especially in early stages.

Although it remains unknown whether the cause(s) of CKDu are related to environmental and/or occupational exposures, there is similarity (clinically and histologically) to prior outbreaks of environmental toxin-mediated nephropathy. The causes implicated in previous outbreaks of nephropathy have not yet been established as risk factors for CKDu, and further research into novel risk factors and multifactorial etiologies is being pursued.

Challenges in exposure assessment Many recent epidemiological studies examining low-level chronic nephrotoxicants have observed unexpected positive associations with eGFR, a direction opposite to that expected with exposure to a nephrotoxicant [23, 83, 101, 102]. This association is more often observed with serum creatinine-based eGFR and when urinary levels of a nephrotoxicant (exposure) are adjusted for urine concentration using creati-nine, and it has been highlighted in a recent review [103]. The mechanism or mechanisms for this unexpected association remain unclear. Hypotheses include the possibility of reverse causality, as discussed earlier in this review. It is also possible that biomarker concentrations could be impacted by any level of GFR, even when in the normal physiologic range. If this were to be true, it could have important implications on any research which utilizes urinary biomarkers and may indicate a need to adjust for GFR, even in healthy populations. Other hypotheses to account for these unexpected positive associations could be a statistical interaction using correlated bio-markers, such as serum and urine creatinine in exposure and outcome variables, or potentially the impact of kidney tubule processing of urinary creatinine, which may be differentially affected by metal exposure.

Because kidney function is affected by multiple exposures and host characteristics, the causal contribution of a single putative environmental nephrotoxicant can be difficult to isolate, particularly when the exposures are chronic and low-level. Large population studies are necessary to achieve the statistical power needed to overcome imprecise outcome measures and the possibility of simultaneous exposure to multiple nephrotoxic exposures. Inconsistent results and/or weak correlations are to be expected, particularly as smaller and smaller outcome effects are evaluated. Consequently, the findings of statistical significance for some but not all biomarkers do not necessarily invalidate the importance of positive

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associations observed. There remains an obligation to recognize the potential importance of Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author statistically significant findings in environmental epidemiological research and acknowledge that many exposures have been understudied. It is imperative to be vigilant with preventative strategies, the cornerstone of risk mitigation and public health.

Conclusions There is a growing awareness of the adverse effects of a multitude of potential nephrotoxicants, including heavy metals and other chemicals or substances found in the environment, on kidney health in children. Several key challenges remain in this area of research. There continues to be a paucity of high-quality epidemiological studies designed to assess environmental exposures in children with multiple health outcomes, kidney and otherwise. Barriers include lack of statistical power due to small sample sizes, quality of exposure assessment, adequate control of potential confounders, and freedom from bias. Further work into the unexpected positive associations between urinary biomarkers and kidney outcomes is necessary. As environmental exposures are modifiable, in contrast to most causes of acute and CKD, well-designed epidemio-logical studies should be prioritized in order to further our understanding of and to characterize relationships between potential nephrotoxic exposures and health outcomes in children. Clinicians should be cognizant that environmental exposures are relatively common and be vigilant in screening. A targeted history based on the exposure sources for the potential toxicants in Table 1 should be performed for each patient, and if there is concern for exposure, a more detailed exposure assessment can be considered.

Multiple choice questions (answers are provided following the references) 1. Which of the following is TRUE regarding the epidemiology of kidney disease due to environmental exposures?

a. Cadmium and lead co-exposure is associated with a significantly higher risk of albuminuria and CKD than either exposure alone.

b. Aristolochic acid nephropathy is associated with acute tubular injury but has not been associated with ESRD.

c. Chelation studies in patients with lead nephropathy have been overall disappointing, with no evidence of improvement in GFR with chelation therapy.

d. Most of the known environmental toxins primarily affect the glomerulus.

2. Which of the following have been proposed as possible etiologies of CKDu?

a. Infections.

b. Recurrent dehydration.

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c. Pesticides. Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author d. Chronic NSAID exposure. e. All of the above. 3. What is the proposed mechanism of acute kidney injury and nephrotoxicity of melamine?

a. Proximal tubulopathy. b. Immune-complex-mediated glomerulonephritis.

c. Urinary obstruction from melamine-induced urinary stones.

d. Chronic tubulointerstitial nephritis. 4. Which of the following heavy metals are not known to accumulate in the body (bioaccumulative) after exposure?

a. Lead. b. Cadmium. c. Arsenic. d. Uranium. 5. Which of the following is NOT a known exposure to lead in the modern world?

a. Residential paint. b. Gasoline. c. Dental amalgams. d. Mining operations. e. Plumbing. Answers

1: a

2: e

3: c

4: c

5: c

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Author ManuscriptAuthor References Manuscript Author Manuscript Author Manuscript Author 1. U.S. Environmental Protection Agency (EPA). Chemical hazard environmental study: What do we really know about the safety of high production volume chemicals?. Office of Pollution Prevention and Toxics; Washington DC: 1998. Available at: http://www.epa.gov/hpv/pubs/general/hazchem.pdf 2. Woodruff TJ, Zota AR, Schwartz JM. Environmental chemicals in pregnant women in the United States: NHANES 2003–2004. Environ Health Perspect. 2011; 119:878–885. [PubMed: 21233055] 3. Schreuder MF. Safety in glomerular numbers. Pediatr Nephrol. 2012; 27:1881–1887. [PubMed: 22532329] 4. Schwartz GJ, Furth SL. Glomerular filtration rate measurement and estimation in chronic kidney disease. Pediatr Nephrol. 2007; 22:1839–1848. [PubMed: 17216261] 5. Solhaug MJ, Bolger PM, Jose PA. The developing kidney and environmental toxins. Pediatrics. 2004; 113:1084–1091. [PubMed: 15060203] 6. Etzel, RA.; Landrigan, PJ. Children’s exquisite vulnerability to environmental exposures. In: Landrigan, PJ.; Etzel, RA., editors. Children’s environmental health. Oxford University Press; New York: 2013. p. 18-27. 7. Wigle DT, Arbuckle TE, Walker M, Wade MG, Liu S, Krewski D. Environmental hazards: evidence for effects on child health. J Toxicol Environ Health B Crit Rev. 2007; 10:3–39. [PubMed: 18074303] 8. Landrigan PJ. Children as a vulnerable population. Int J Occup Med Environ Health. 2004; 17:175– 177. [PubMed: 15212221] 9. Ginsberg G, Hattis D, Sonawane B, Russ A, Banati P, Kozlak M, Smolenski S, Goble R. Evaluation of child/adult pharma-cokinetic differences from a database derived from the therapeutic drug literature. Toxicol Sci. 2002; 66:185–200. [PubMed: 11896285] 10. Sabolic I. Common mechanisms in nephropathy induced by toxic metals. Nephron Physiol. 2006; 104:p107–p114. [PubMed: 16940748] 11. Agency for Toxic Substance & Disease Registry (ATSDR) AfTSaDR. Toxicological profile for arsenic. U.S. Department of Health and Human Services and Public Health Service; Atlanta: 2007. Available at: http://www.atsdr.cdc.gov/ToxProfiles/TP.asp?id=22&tid=3 [6/10/2015] 12. Prasad GV, Rossi NF. Arsenic intoxication associated with tubulointerstitial nephritis. Am J Kidney Dis. 1995; 26:373–376. [PubMed: 7645544] 13. Agency EP. National primary drinking water regulations; arsenic and clarifications to compliance and new source contaminants monitoring; final rule. Fed Regist. 2001; 66:6976–7066. 14. Zheng L, Kuo CC, Fadrowski J, Agnew J, Weaver VM, Navas-Acien A. Arsenic and chronic kidney disease: a systematic review. Curr Environ Health Rep. 2014; 1:192–207. [PubMed: 25221743] 15. Zheng LY, Umans JG, Yeh F, Francesconi KA, Goessler W, Silbergeld EK, Bandeen-Roche K, Guallar E, Howard BV, Weaver VM, Navas-Acien A. The association of urine arsenic with prevalent and incident chronic kidney disease: evidence from the Strong Heart Study. Epidemiology. 2015; 6(4):601–612. DOI: 10.1097/EDE.0000000000000313 [PubMed: 25929811] 16. Chen JW, Chen HY, Li WF, Liou SH, Chen CJ, Wu JH, Wang SL. The association between total urinary arsenic concentration and renal dysfunction in a community-based population from central Taiwan. Chemosphere. 2011; 84:17–24. [PubMed: 21458841] 17. Hsueh YM, Chung CJ, Shiue HS, Chen JB, Chiang SS, Yang MH, Tai CW, Su CT. Urinary arsenic species and CKD in a Taiwanese population: a case–control study. Am J Kidney Dis. 2009; 54:859–870. [PubMed: 19682779] 18. Huang CY, Chu JS, Pu YS, Yang HY, Wu CC, Chung CJ, Hsueh YM. Effect of urinary total arsenic level and estimated glomerular filtration rate on the risk of renal cell carcinoma in a low arsenic exposure area. J Urol. 2011; 185:2040–2044. [PubMed: 21496841] 19. Smith AH, Marshall G, Liaw J, Yuan Y, Ferreccio C, Steinmaus C. Mortality in young adults following in utero and childhood exposure to arsenic in drinking water. Environ Health Perspect. 2012; 120:1527–1531. [PubMed: 22949133] 20. de Burbure C, Buchet JP, Leroyer A, Nisse C, Haguenoer JM, Mutti A, Smerhovsky Z, Cikrt M, Trzcinka-Ochocka M, Razniewska G, Jakubowski M, Bernard A. Renal and neurologic effects of

Pediatr Nephrol. Author manuscript; available in PMC 2017 November 01. Weidemann et al. Page 15

cadmium, lead, mercury, and arsenic in children: evidence of early effects and multiple Author ManuscriptAuthor Manuscript Author Manuscriptinteractions Author at environmental Manuscript Author exposure levels. Environ Health Perspect. 2006; 114:584–590. [PubMed: 16581550] 21. Hawkesworth S, Wagatsuma Y, Kippler M, Fulford AJ, Arifeen SE, Persson LA, Moore SE, Vahter M. Early exposure to toxic metals has a limited effect on blood pressure or kidney function in later childhood, rural Bangladesh. Int J Epidemiol. 2013; 42:176–185. [PubMed: 23243118] 22. Skroder H, Hawkesworth S, Kippler M, El Arifeen S, Wagatsuma Y, Moore SE, Vahter M. Kidney function and blood pressure in preschool-aged children exposed to cadmium and arsenic— potential alleviation by selenium. Environ Res. 2015; 140:205–213. [PubMed: 25863594] 23. Weidemann D, Kuo CC, Navas-Acien A, Abraham AG, Weaver V, Fadrowski J. Association of arsenic with kidney function in adolescents and young adults: results from the national health and nutrition examination survey 2009–2012. Environ Res. 2015; 140:317–324. [PubMed: 25909687] 24. Jarup L, Akesson A. Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol. 2009; 238:201–208. [PubMed: 19409405] 25. Richter PA, Bishop EE, Wang J, Swahn MH. Tobacco smoke exposure and levels of urinary metals in the U.S. youth and adult population: the national health and nutrition examination survey (NHANES) 1999–2004. Int J Environ Res Public Health. 2009; 6:1930–1946. [PubMed: 19742163] 26. Roels HA, Van Assche FJ, Oversteyns M, De Groof M, Lauwerys RR, Lison D. Reversibility of microproteinuria in cadmium workers with incipient tubular dysfunction after reduction of exposure. Am J Ind Med. 1997; 31:645–652. [PubMed: 9099369] 27. Li Q, Nishijo M, Nakagawa H, Morikawa Y, Sakurai M, Nakamura K, Kido T, Nogawa K, Dai M. Relationship between urinary cadmium and mortality in habitants of a cadmium-polluted area: a 22-year follow-up study in Japan. Chin Med J (Engl). 2011; 124:3504–3509. [PubMed: 22340168] 28. Akesson A, Lundh T, Vahter M, Bjellerup P, Lidfeldt J, Nerbrand C, Samsioe G, Stromberg U, Skerfving S. Tubular and glomerular kidney effects in Swedish women with low environmental cadmium exposure. Environ Health Perspect. 2005; 113:1627–1631. [PubMed: 16263522] 29. Hellstrom L, Elinder CG, Dahlberg B, Lundberg M, Jarup L, Persson B, Axelson O. Cadmium exposure and end-stage renal disease. Am J Kidney Dis. 2001; 38:1001–1008. [PubMed: 11684553] 30. Navas-Acien A, Tellez-Plaza M, Guallar E, Muntner P, Silbergeld E, Jaar B, Weaver V. Blood cadmium and lead and chronic kidney disease in US adults: a joint analysis. Am J Epidemiol. 2009; 170:1156–1164. [PubMed: 19700501] 31. Staessen JA, Nawrot T, Hond ED, Thijs L, Fagard R, Hoppenbrouwers K, Koppen G, Nelen V, Schoeters G, Vanderschueren D, Van Hecke E, Verschaeve L, Vlietinck R, Roels HA. Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: a feasibility study of biomarkers. Lancet. 2001; 357:1660–1669. [PubMed: 11425371] 32. Noonan CW, Sarasua SM, Campagna D, Kathman SJ, Lybarger JA, Mueller PW. Effects of exposure to low levels of environmental cadmium on renal biomarkers. Environ Health Perspect. 2002; 110:151–155. [PubMed: 11836143] 33. Registry AfTSaD. Public Health Statement for Lead. CAS# 7439-92-1. US Department of Health and Human Services/Public Health Service; Atlanta: 2007. Available at: http:// www.atsdr.cdc.gov/PHS/PHS.asp?id=92&tid=22 [6 Oct 2015] 34. Cramer K, Goyer RA, Jagenburg R, Wilson MH. Renal ultrastructure, renal function, and parameters of lead toxicity in workers with different periods of lead exposure. Br J Ind Med. 1974; 31:113–127. [PubMed: 4830763] 35. Goyer RA. Mechanisms of lead and cadmium nephrotoxicity. Toxicol Lett. 1989; 46:153–162. [PubMed: 2650022] 36. Hu H, Rabinowitz M, Smith D. Bone lead as a biological marker in epidemiologic studies of chronic toxicity: conceptual paradigms. Environ Health Perspect. 1998; 106:1–8. [PubMed: 9417769]

Pediatr Nephrol. Author manuscript; available in PMC 2017 November 01. Weidemann et al. Page 16

37. Rosen JF, Chesney RW, Hamstra A, DeLuca HF, Mahaffey KR. Reduction in 1,25- Author ManuscriptAuthor Manuscript Author Manuscriptdihydroxyvitamin Author D Manuscript Author in children with increased lead absorption. N Engl J Med. 1980; 302:1128– 1131. [PubMed: 7366636] 38. Chisolm JJHH, Eberlein WR, Harrison HE. Aminoaciduria, hypophosphatemia, and rickets in lead poisoning. Am J Dis Child. 1955; 89:159–168. 39. Khalil-Manesh F, Gonick HC, Cohen A, Bergamaschi E, Mutti A. Experimental model of lead nephropathy. II. Effect of removal from lead exposure and chelation treatment with dimercaptosuccinic acid (DMSA). Environ Res. 1992; 58:35–54. [PubMed: 1317791] 40. Ekong EB, Jaar BG, Weaver VM. Lead-related nephrotoxicity: a review of the epidemiologic evidence. Kidney Int. 2006; 70:2074–2084. [PubMed: 17063179] 41. Loghman-Adham M. Renal effects of environmental and occupational lead exposure. Environ Health Perspect. 1997; 105:928–938. [PubMed: 9300927] 42. Morgan JM, Hartley MW, Miller RE. Nephropathy in chronic lead poisoning. Arch Intern Med. 1966; 118:17–29. [PubMed: 5940188] 43. Aviv A, John E, Bernstein J, Goldsmith DI, Spitzer A. Lead intoxication during development: its late effects on kidney function and blood pressure. Kidney Int. 1980; 17:430–437. [PubMed: 7392418] 44. Nowack R, Wiecek A, Ritz E. Lead and hypertension. Contrib Nephrol. 1992; 100:25–34. [PubMed: 1458905] 45. Nye LJ. An investigation of the extraordinary incidence of chronic nephritis in young people in Queensland. Med J Aust. 1929; 2:145–159. 46. Henderson DA. A follow-up of cases of plumbism in children. Australas Ann Med. 1954; 3:219– 224. [PubMed: 13198776] 47. Inglis JA, Henderson DA, Emmerson BT. The pathology and pathogenesis of chronic lead nephropathy occurring in Queensland. J Pathol. 1978; 124:65–76. [PubMed: 363988] 48. Emmerson BT. Chronic lead nephropathy. Kidney Int. 1973; 4:1–5. [PubMed: 4353288] 49. Kimmelstiel P, Wilson C. Benign and malignant hypertension and nephrosclerosis: a clinical and pathological study. Am J Pathol. 1936; 12(45–82):43. 50. Hu H. A 50-year follow-up of childhood plumbism. Hypertension, renal function, and hemoglobin levels among survivors. Am J Dis Child. 1991; 145:681–687. [PubMed: 2035497] 51. Moel DI, Sachs HK, Cohn RA, Drayton MA. Renal function 9 to 17 years after childhood lead poisoning. J Pediatr. 1985; 106:729–733. [PubMed: 3998912] 52. Loghman-Adham M. Aminoaciduria and glycosuria following severe childhood lead poisoning. Pediatr Nephrol. 1998; 12:218–221. [PubMed: 9630041] 53. Moel DI, Sachs HK. Renal function 17 to 23 years after chelation therapy for childhood plumbism. Kidney Int. 1992; 42:1226–1231. [PubMed: 1453607] 54. Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol. 2012; 8:293–300. [PubMed: 22349487] 55. Khalil-Manesh F, Gonick HC, Cohen AH, Alinovi R, Bergamaschi E, Mutti A, Rosen VJ. Experimental model of lead nephropathy. I. Continuous high-dose lead administration. Kidney Int. 1992; 41:1192–1203. [PubMed: 1614034] 56. Weaver VM, Lee BK, Ahn KD, Lee GS, Todd AC, Stewart WF, Wen J, Simon DJ, Parsons PJ, Schwartz BS. Associations of lead biomarkers with renal function in Korean lead workers. Occup Environ Med. 2003; 60:551–562. [PubMed: 12883015] 57. Bernard AM, Vyskocil A, Roels H, Kriz J, Kodl M, Lauwerys R. Renal effects in children living in the vicinity of a lead smelter. Environ Res. 1995; 68:91–95. [PubMed: 7601077] 58. Fels LM, Wunsch M, Baranowski J, Norska-Borowka I, Price RG, Taylor SA, Patel S, De Broe M, Elsevier MM, Lauwerys R, Roels H, Bernard A, Mutti A, Gelpi E, Rosello J, Stolte H. Adverse effects of chronic low level lead exposure on kidney function—-a risk group study in children. Nephrol Dial Transplant. 1998; 13:2248–2256. [PubMed: 9761504] 59. Verberk MM, Willems TE, Verplanke AJ, De Wolff FA. Environmental lead and renal effects in children. Arch Environ Health. 1996; 51:83–87. [PubMed: 8629869]

Pediatr Nephrol. Author manuscript; available in PMC 2017 November 01. Weidemann et al. Page 17

60. Factor-Litvak P, Wasserman G, Kline JK, Graziano J. The Yugoslavia prospective study of Author ManuscriptAuthor Manuscript Author Manuscriptenvironmental Author lead exposure. Manuscript Author Environ Health Perspect. 1999; 107:9–15. [PubMed: 9872712] 61. Chisolm JJ Jr. The road to primary prevention of lead toxicity in children. Pediatrics. 2001; 107:581–583. [PubMed: 11230602] 62. Muntner P, He J, Vupputuri S, Coresh J, Batuman V. Blood lead and chronic kidney disease in the general United States population: results from NHANES III. Kidney Int. 2003; 63:1044–1050. [PubMed: 12631086] 63. Payton M, Hu H, Sparrow D, Young JB, Landsberg L, Weiss ST. Relation between blood lead and urinary biogenic amines in community-exposed men. Am J Epidemiol. 1993; 138:815–825. [PubMed: 8237970] 64. Staessen JA, Lauwerys RR, Buchet JP, Bulpitt CJ, Rondia D, Vanrenterghem Y, Amery A. Impairment of renal function with increasing blood lead concentrations in the general population. The Cadmibel Study Group. N Engl J Med. 1992; 327:151–156. [PubMed: 1608406] 65. Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E. Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. Circulation. 2006; 114:1388–1394. [PubMed: 16982939] 66. Fadrowski JJ, Navas-Acien A, Tellez-Plaza M, Guallar E, Weaver VM, Furth SL. Blood lead level and kidney function in US adolescents: the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2010; 170:75–82. [PubMed: 20065202] 67. Fadrowski JJ, Abraham AG, Navas-Acien A, Guallar E, Weaver VM, Furth SL. Blood lead level and measured glomerular filtration rate in children with chronic kidney disease. Environ Health Perspect. 2013; 121:965–970. [PubMed: 23694739] 68. Filler G, Roach E, Yasin A, Sharma AP, Blake PG, Yang L. High prevalence of elevated lead levels in pediatric dialysis patients. Pediatr Nephrol. 2012; 27:1551–1556. [PubMed: 22527529] 69. Yu CC, Lin JL, Lin-Tan DT. Environmental exposure to lead and progression of chronic renal diseases: a four-year prospective longitudinal study. J Am Soc Nephrol. 2004; 15:1016–1022. [PubMed: 15034104] 70. Scharer K, Veits G, Brockhaus A, Ewers U. High lead content of deciduous teeth in chronic renal failure. Pediatr Nephrol. 1991; 5:704–707. [PubMed: 1768582] 71. Lin-Tan DT, Lin JL, Yen TH, Chen KH, Huang YL. Long-term outcome of repeated lead chelation therapy in progressive non-diabetic chronic kidney diseases. Nephrol Dial Transplant. 2007; 22:2924–2931. [PubMed: 17556414] 72. Lin JL, Lin-Tan DT, Yu CC, Li YJ, Huang YY, Li KL. Environmental exposure to lead and progressive diabetic nephropathy in patients with type II diabetes. Kidney Int. 2006; 69:2049– 2056. [PubMed: 16641918] 73. Weaver VM, Fadrowski JJ, Jaar BG. Does calcium disodium EDTA slow CKD progression? Am J Kidney Dis. 2012; 60:503–506. [PubMed: 22985977] 74. Landrigan, PJ.; Etzel, RA. Textbook of children’s environmental health. Oxford University Press; Oxford: 2014. 75. Hua J, Pelletier L, Berlin M, Druet P. Autoimmune glomerulonephritis induced by mercury vapour exposure in the Brown Norway rat. Toxicology. 1993; 79:119–129. [PubMed: 8497865] 76. Li SJ, Zhang SH, Chen HP, Zeng CH, Zheng CX, Li LS, Liu ZH. Mercury-induced membranous nephropathy: clinical and pathological features. Clin J Am Soc Nephrol. 2010; 5:439–444. [PubMed: 20089494] 77. Barregard L, Trachtenberg F, McKinlay S. Renal effects of dental amalgam in children: the New England Children’s Amalgam Trial. Environ Health Perspect. 2008; 116:394–399. [PubMed: 18335109] 78. Woods JS, Martin MD, Leroux BG, DeRouen TA, Bernardo MF, Luis HS, Leitao JG, Kushleika JV, Rue TC, Korpak AM. Biomarkers of kidney integrity in children and adolescents with dental amalgam mercury exposure: findings from the Casa Pia Children’s Amalgam Trial. Environ Res. 2008; 108:393–399. [PubMed: 18721920] 79. Geier DA, Carmody T, Kern JK, King PG, Geier MR. A significant dose-dependent relationship between mercury exposure from dental amalgams and kidney integrity biomarkers: a further

Pediatr Nephrol. Author manuscript; available in PMC 2017 November 01. Weidemann et al. Page 18

assessment of the Casa Pia Children’s Dental Amalgam. Trial Hum Exp Toxicol. 2013; 32:434– Author ManuscriptAuthor Manuscript Author Manuscript440. Author [PubMed: 22893351] Manuscript Author 80. DeRouen TA, Woods JS, Leroux BG, Martin MD. Critique of reanalysis of Casa Pia data on associations of porphyrins and glutathione-S-transferases with dental amalgam exposure. Hum Exp Toxicol. 2015; 34:330–332. [PubMed: 25005805] 81. Arzuaga X, Rieth SH, Bathija A, Cooper GS. Renal effects of exposure to natural and depleted uranium: a review of the epidemiologic and experimental data. J Toxicol Environ Health B Crit Rev. 2010; 13:527–545. [PubMed: 21170808] 82. Homma-Takeda S, Kitahara K, Suzuki K, Blyth BJ, Suya N, Konishi T, Terada Y, Shimada Y. Cellular localization of uranium in the renal proximal tubules during acute renal uranium toxicity. J Appl Toxicol. 2015; doi: 10.1002/jat.3126 83. Shelley R, Kim NS, Parsons PJ, Lee BK, Agnew J, Jaar BG, Steuerwald AJ, Matanoski G, Fadrowski J, Schwartz BS, Todd AC, Simon D, Weaver VM. Uranium associations with kidney outcomes vary by urine concentration adjustment method. J Expo Sci Environ Epidemiol. 2014; 24:58–64. [PubMed: 23591699] 84. McDiarmid MA, Engelhardt SM, Dorsey CD, Oliver M, Gucer P, Wilson PD, Kane R, Cernich A, Kaup B, Anderson L, Hoover D, Brown L, Albertini R, Gudi R, Squibb KS. Surveillance results of depleted uranium-exposed Gulf War I veterans: sixteen years of follow-up. J Toxicol Environ Health A. 2009; 72:14–29. [PubMed: 18979351] 85. Magdo HS, Forman J, Graber N, Newman B, Klein K, Satlin L, Amler RW, Winston JA, Landrigan PJ. Grand rounds: nephrotoxicity in a young child exposed to uranium from contaminated well water. Environ Health Perspect. 2007; 115:1237–1241. [PubMed: 17687453] 86. Arlt VM, Stiborova M, Schmeiser HH. Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis. 2002; 17:265–277. [PubMed: 12110620] 87. Hong YT, Fu LS, Chung LH, Hung SC, Huang YT, Chi CS. Fanconi’s syndrome, interstitial fibrosis and renal failure by aristolochic acid in Chinese herbs. Pediatr Nephrol. 2006; 21:577– 579. [PubMed: 16520953] 88. De Broe ME. Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy. Kidney Int. 2012; 81:513–515. [PubMed: 22373701] 89. U.S. Food and Drug Administration (FDA). Aristolochic acid: FDA warns consumers to discontinue use of botanical products that contain aristolochic acid. Consumer Advisory, FDA; Washington DC: 2011. Available at: http://www.fda.gov/Food/RecallsOutbreaksEmergencies/ SafetyAlertsAdvisories/ucm096388.htm [10 June 2015] 90. Gokmen MR, Cosyns JP, Arlt VM, Stiborova M, Phillips DH, Schmeiser HH, Simmonds MS, Cook HT, Vanherweghem JL, Nortier JL, Lord GM. The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review. Ann Intern Med. 2013; 158:469– 477. [PubMed: 23552405] 91. Bennett JW, Klich M. Mycotoxins. Clin Microbiol Rev. 2003; 16:497–516. [PubMed: 12857779] 92. Berndt WO. The role of transport in chemical nephrotoxicity. Toxicol Pathol. 1998; 26:52–57. [PubMed: 9502387] 93. Dalal RP, Goldfarb DS. Melamine-related kidney stones and renal toxicity. Nat Rev Nephrol. 2011; 7:267–274. [PubMed: 21423252] 94. Gossner CM, Schlundt J, Ben Embarek P, Hird S, Lo-Fo-Wong D, Beltran JJ, Teoh KN, Tritscher A. The melamine incident: implications for international food and feed safety. Environ Health Perspect. 2009; 117:1803–1808. [PubMed: 20049196] 95. Hau AK, Kwan TH, Li PK. Melamine toxicity and the kidney. J Am Soc Nephrol. 2009; 20:245– 250. [PubMed: 19193777] 96. Correa-Rotter R, Wesseling C, Johnson RJ. CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy. Am J Kidney Dis. 2014; 63:506–520. [PubMed: 24412050] 97. Wijkstrom J, Leiva R, Elinder CG, Leiva S, Trujillo Z, Trujillo L, Soderberg M, Hultenby K, Wernerson A. Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America. Am J Kidney Dis. 2013; 62:908–918. [PubMed: 23850447] 98. Weiner DE, McClean MD, Kaufman JS, Brooks DR. The Central American epidemic of CKD. Clin J Am Soc Nephrol. 2013; 8:504–511. [PubMed: 23099656]

Pediatr Nephrol. Author manuscript; available in PMC 2017 November 01. Weidemann et al. Page 19

99. Jayasekara JM, Dissanayake DM, Adhikari SB, Bandara P. Geographical distribution of chronic Author ManuscriptAuthor Manuscript Author Manuscriptkidney Author disease of unknown Manuscript Author origin in North Central Region of Sri Lanka. Ceylon Med J. 2013; 58:6–10. [PubMed: 23549716] 100. Ramírez-Rubio, OBDAJ.; Kaufman, J.; Weiner, D.; Parkh, C.; Khan, U.; McClean, M.; Laws, R. [10 June 2015] Biomarkers of early kidney damage in Nicaraguan adolescents September– November 2011. Independent report of the Office of Compliance Advisor/Ombudsman. 2012. Available at: http://www.cao-ombudsman.org/cases/document-links/documents/ AdolescentReportJune252012.pdf 101. Weaver VM, Vargas GG, Silbergeld EK, Rothenberg SJ, Fadrowski JJ, Rubio-Andrade M, Parsons PJ, Steuerwald AJ, Navas-Acien A, Guallar E. Impact of urine concentration adjustment method on associations between urine metals and estimated glomerular filtration rates (eGFR) in adolescents. Environ Res. 2014; 132:226–232. [PubMed: 24815335] 102. Shelley R, Kim NS, Parsons P, Lee BK, Jaar B, Fadrowski J, Agnew J, Matanoski GM, Schwartz BS, Steuerwald A, Todd A, Simon D, Weaver VM. Associations of multiple metals with kidney outcomes in lead workers. Occup Environ Med. 2012; 69:727–735. [PubMed: 22843435] 103. Weaver VM, Kotchmar DJ, Fadrowski JJ, Silbergeld EK. Challenges for environmental epidemiology research: are bio-marker concentrations altered by kidney function or urine concentration adjustment? J Expos Sci Environ Epidemiol. 2015; doi: 10.1038/jes.2015.8

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Fig. 1. The nephron and associated sites of action of various nephrotoxicants. NSAIDs Nonsteroidal anti-inflammatory drugs. Adapted from: Lote C (2012) Principles of renal physiology, 5th edn, Springer, New York, p 23, with permission

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Fig. 2. Histopathology of a patient with chronic lead nephropathy, characterized by a normal glomerulus, nonspecific tubular atrophy, and interstitial fibrosis. (Image courtesy of Vecihi Batuman)

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Table 1

Author ManuscriptAuthor Environmental Manuscript Author exposure Manuscript Author to nephrotoxicants Manuscript Author and associated kidney disease manifestations

Agent Source of exposure Short-term (acute toxicity) Long-term (chronic exposure) Lead Lead-based paint; soil and dust (paint, Fanconi’s syndrome Lead nephropathy, CKD gasoline, industrial sources); drinking water (lead pipes), cigarette smoke Arsenic Groundwater contamination; food Acute tubular necrosis CKD; kidney cancer contamination (apple juice, rice, wine) Cadmium Fossil fuel combustion; phosphate fertilizers; Acute tubular necrosis CKD iron and steel production; batteries; municipal solid waste incineration; food contamination (rice, root crops) Mercury Coal-fired power plants; smelters, gold Acute tubular necrosis; immune- Limited evidence; possibly production; municipal waste incineration; complex mediated nephritic microalbuminuria natural sources (volcanoes) syndrome Uranium Groundwater contamination of natural Acute tubular necrosis Limited evidence; proximal tubular uranium deposits; uranium mining, milling, injury (²-2 microgobulin) and processing Aristolochic acid Aristolochiaceae family of plants (used in Interstitial nephritis Interstitial nephritis; urothelial Chinese herbs) carcinoma Melamine Food adulterant; manufacture of colorants, Urinary stones, acute kidney No long-term known outcomes glues, laminates, adhesives, dinnerware, dry- injury described erase boards, cleaning products, and flame retardants

CKD, Chronic kidney disease

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